This project has two goals. One is to uncover and describe naturally occurring delayed-type iso-hypersensitivies (DIH) towards heritable iso-antigens to determine the function of DIH, and to seek health-oriented conditions controlled by DIH. Three instances of isoreactivity have been described. In guinea pigs DIH can be detected by delayed dermal reactions to an iso-antigenic heritable serum factor. The other two, in mice, are revealed by T cells that replicate in the presence of mitomycin-treated, isogeneic adult splenic cells. We are concentrating attention on these latter two isogeneic lymphocyte interactions by studying the maturation of the differentiation markers on bone marrow cells that stimulate the T cell replication and by examining the maturing BM cells for function. The other objective is to reveal principles of immuno-regulation. For this pupose, we have three separate systems. Using dextran as an immuno-probe we have found it markedly changes humoral antibody and delayed hypersensitivity responses to unrelated antigens. Certain of these alterations are caused by T cell products, the release of which is triggered by dextran. Furthermore, dextran interrupts the T cell helper signal that B cells require to the extent of splenic influence on immuno-competence. Congenitally spleenless mice synthesize depressed amounts of IgM and IgG antibodies but demonstrate intact delayed-type hypersensitivity and tolerance induction. Bone marrow and thymic cells from asplenic mice were found to be incapable of making normal antibody responses. Furthermore, lymph node cells from two-thirds of asplenic mice were found to be deficient in synergy for cell-mediated lympholysis. The third system we use to study immuno-regulation is through the IgG recruiting component (GRC) derived from B cells. GRC, most plentiful during secondary immune responses, has been found to augment IgG synthesis during a primary immune response. It is active on B cells only after AEF has had its input. We plan to characterize GRC more fully.